There is strong evidence that cytokines play a key role in the pathogenesis of Crohn's disease (CD). During the previous funding period, we demonstrated that TNF and IL-4 are important mediators of chronic ileitis in SAMP1/YitFc (SAMP) mice. These unique mice spontaneously develop enteritis without the need for genetic or immunological manipulation, and display macroscopic and histological features closely resembling CD. The overall objective of Project 1 is to continue to investigate the expression and function of key pathogenic cytokines involved in the pathogenesis of chronic intestinal inflammation in this spontaneous murine model of CD. In order to achieve our goals we will: 1) Determine the expression and cellular localization of novel cvtokines during ileitis in SAMP mice. We will clearly define the expression, localization, time course, and cellular origin of TL1A, a novel TNF-like factor, and IL-13, a prototypic Th2 cytokine, as well as their receptors, using real-time PCR, ELISA techniques, immunocytochemistry and multi-color FACS analysis. 2) Define the function of these novel cvtokines in the intestinal mucosa of SAMP mice. We will study the ability of TL1A and IL-13 to stimulate the production of IFN-gamma and other adaptive cytokines in isolated mucosal cells (MLN and LPL) and peripheral lymphocytes from SAMP mice. In addition, we will study how TL1A and IL-13 affect epithelial cell function, cytokine production and barrier function, using ex vivo permeability studies. 3) Determine the effect of cvtokine manipulation on the severity of ileitis in SAMP mice. We will investigate the effects of TL1A and IL-13 neutralization using monoclonal antibodies and a novel siRNA gene shutdown retroviral delivery system. We will also generate DR3 or IL-13-deficient SAMP mice to further define the role of these cytokines in the initiation and perpetuation of chronic ileitis in this model. The ultimate goal of Project 1 is to define the key pathogenic role of cytokines in experimental CD, in order to develop disease-modifying treatment modalities for this devastating disease.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Program Projects (P01)
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Special Emphasis Panel (ZDK1-GRB-2 (M3))
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University of Virginia
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Ernst, P B; Erickson, L D; Loo, W M et al. (2012) Spontaneous autoimmune gastritis and hypochlorhydria are manifest in the ileitis-prone SAMP1/YitFcs mice. Am J Physiol Gastrointest Liver Physiol 302:G105-15
Lou, Yuefen; Lu, Xiaojiong; Dang, Xitong (2012) FOXO1 Up-Regulates Human L-selectin Expression Through Binding to a Consensus FOXO1 Motif. Gene Regul Syst Bio 6:139-49
Reuter, Brian K; Pastorelli, Luca; Brogi, Marco et al. (2011) Spontaneous, immune-mediated gastric inflammation in SAMP1/YitFc mice, a model of Crohn's-like gastritis. Gastroenterology 141:1709-19
Pizarro, Theresa T; Pastorelli, Luca; Bamias, Giorgos et al. (2011) SAMP1/YitFc mouse strain: a spontaneous model of Crohn's disease-like ileitis. Inflamm Bowel Dis 17:2566-84
Shanahan, Michael T; Vidrich, Alda; Shirafuji, Yoshinori et al. (2010) Elevated expression of Paneth cell CRS4C in ileitis-prone SAMP1/YitFc mice: regional distribution, subcellular localization, and mechanism of action. J Biol Chem 285:7493-504
Pastorelli, Luca; Garg, Rekha R; Hoang, Sharon B et al. (2010) Epithelial-derived IL-33 and its receptor ST2 are dysregulated in ulcerative colitis and in experimental Th1/Th2 driven enteritis. Proc Natl Acad Sci U S A 107:8017-22
Gorfu, Gezahegn; Rivera-Nieves, Jesus; Hoang, Sharon et al. (2010) Beta7 integrin deficiency suppresses B cell homing and attenuates chronic ileitis in SAMP1/YitFc mice. J Immunol 185:5561-8
Gorfu, G; Rivera-Nieves, J; Ley, K (2009) Role of beta7 integrins in intestinal lymphocyte homing and retention. Curr Mol Med 9:836-50
Vidrich, Alda; Buzan, Jenny M; Brodrick, Brooks et al. (2009) Fibroblast growth factor receptor-3 regulates Paneth cell lineage allocation and accrual of epithelial stem cells during murine intestinal development. Am J Physiol Gastrointest Liver Physiol 297:G168-78
Reuter, Brian K; Pizarro, Theresa T (2009) Mechanisms of tight junction dysregulation in the SAMP1/YitFc model of Crohn's disease-like ileitis. Ann N Y Acad Sci 1165:301-7

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